This grant seeks to address important clinical and scientific questions regarding human hearing diseases and their treatment. To do so, we make simultaneous pressure measurements on each side of the cochlear partition in human cadaveric temporal bones. This new and powerful technique enables direct determination of the differential pressure across the cochlear partition, the stimulus that excites the cochlear partition and initiates the cochlear traveling wave. Thus, this intracochlear differential pressure measurement in cadaveric temporal bones allows for a representation of what a live human with normal sensory function would hear, enabling us to investigate human hearing under controlled circumstances and to answer questions which could not be previously addressed, as outlined in the following 3 aims: Aim 1) Determine if a useful level of hearing is possible when the oval window is blocked and the cochlea is stimulated via the round window (RW). The experiments under this aim will establish whether or not RW stimulation can effectively treat stapes fixation in patients where stapedectomy is contraindicated. Furthermore, they will test the degree to which the cochlea can be approximated as a rigid bone containing incompressible fluid with only two flexible windows (oval and round windows) responsible for the pressure difference across the cochlear partition. Aim 2) Understand how pathologic third-window lesions of the inner ear can result in hearing loss. Superior semicircular canal dehiscence (SCD) is a prototypical third window lesion, and it is unknown why some individuals with SCD have hearing loss while others do not. By studying the impact of controlled dehiscences on differential pressure and other measurements, we will test two hypotheses: 1. Pathologic third windows shunt fluid flow away from the cochlea, resulting in decreased pressure difference across the cochlear partition, leading to hearing loss; 2. The size of the dehiscence is a major factor in the determination of the hearing loss. This study will aid in understanding when and how third-window lesions produce hearing loss and determine whether size of the dehiscence is an important variable. The present treatment for SCD is highly invasive and is reserved for debilitating vestibular symptoms only. A novel alternative treatment for SCD-induced hearing loss is addressed as part of Aim 3. Aim 3) Investigate the application of RW stimulation to treat various diseases of the middle and inner ear, including: 1. semicircular canal dehiscence; 2. discontinuity of the ossicular chain; 3. non-aerated middle ear; and 4. stapes fixation (as in Aim 1). By measuring the trans-cochlear differential pressure evoked by RW stimulation in the controlled setting of cadaveric preparations, while simulating various diseased states, we will investigate whether RW stimulation is a feasible and efficacious treatment for various middle- and inner-ear disorders. It is anticipated that the results of the investigations under these three aims will answer fundamental questions regarding human hearing, and yield advances in the clinical diagnosis and treatment of hearing diseases. PUBLIC HEALTH RELEVANCE: This grant addresses mechanisms and treatments of middle- and inner-ear diseases that are common causes of hearing loss. A new measurement technique based on fiberoptic micro- pressure transducers will be employed in human cadaveric specimens to obtain previously unavailable knowledge and test new treatments.